Pigmentation-Independent Susceptibility Loci for Actinic Keratosis Highlighted by Compound Heterozygosity Analysis

Actinic keratosis (AK) is a skin disease frequently found in European elderly, and it represents the precursor of cutaneous squamous cell carcinoma. Our recent genome-wide association study highlighted DNA variants in two pigmentation genes, IRF4 and MC1R, that confer AK risk in Europeans. Here, we performed a genome-wide search for relaxed forms of compound heterozygosity in association with AK using our recently developed software CollapsABEL. In a discovery dataset of 3,193 Dutch Europeans, a total of 15 genetic loci showed genome-wide significant association with AK (P < 1.25 × 10–10). Of those, three loci (6p21.2, 6p12.2, and 6q13) were confirmed in a replication dataset that included 624 additional Dutch Europeans (P < 0.05). These replicated loci harbored six genes (KCNK5/KCNK17, PAQR8/GSTA2, and KCNQ5/KHDC1), none of them known to be involved in pigmentation. A candidate compound heterozygosity analysis for 12 pigmentation loci highlighted SLC24A4 at 14q32.12 as showing significant association with AK (P = 8.83 × 10–9). The four significantly AK-associated compound heterozygosity single-nucleotide polymorphism pairs together explained 4.37% of the total AK variation, which was 2.62 times greater than the two top-associated individual single nucleotide polymorphisms together (1.67%) identified in the previous conventional genome-wide association study. In conclusion, CollapsABEL showed compound heterozygosity in non–pigmentation- and pigmentation-related loci conferring genetic risk of AK.

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